This Challenge Application is directly and completely responsive to Specific Challenge Topic: 03-CA-102 "Biologic Predictors of Progression in Barrett's Esophagus". It comes from a research team with more than two decades of experience investigating Barrett's esophagus (BE), the only established precursor to esophageal adenocarcinoma (EA), a highly lethal malignancy whose incidence has increased more than 600% in three decades. The hypothesis that clonal evolution underlies neoplastic progression has been well accepted for 30 years, but the temporal course of genomic changes during evolution to cancer has rarely been studied in humans in vivo. BE is a unique in vivo model of human intraepithelial neoplasia, and the Seattle BE cohort is one of the largest and best characterized in the world. Our multidisciplinary team encompasses expertise in clinical research, genomics, evolutionary biology, molecular biology, computational biology, epidemiology and biostatistics, including the analysis of complex datasets. Using a nested cohort sampling study design drawing from the above cohort of 456 individuals with BE, of whom 77 already have progressed to EA, we will evaluate the following hypotheses: (1) high-resolution assessment of somatic genomic abnormalities (SGA) using a molecular cytogenomic 2.7 million SNP/probe array can identify novel regions of chromosome abnormalities that can be assessed as biological predictors of progression from BE to EA (Aim 1);(2) the rate of evolution of SGA over time, which we term somatic genomic instability (SGI), will differentiate between persons at high and low risk of developing EA (Aim 2);and (3) SGI and its effect on risk of EA are modulated by key host and environmental risk and protective factors (Aim 3). Our translational research goals are to improve (1) risk stratification for BE progression to EA at the baseline endoscopy using a diagnostic array that can be readily implemented in clinical laboratories, (2) efficiency of endoscopic surveillance for early detection of EA using measures of genomic instability (SGI) that distinguish individuals who will and will not progress to EA, and (3) clinical management of BE by identifying mechanisms by which risk and protective factors modulate progression that lead to non-invasive interventions, including lifestyle changes, to reduce the incidence and mortality of EA. PUBLIC HEALTH RELEVANCE: Barrett's esophagus is the only known precursor to esophageal adenocarcinoma, a highly lethal cancer that has been increasing at an alarming rate in the United States, but most people with Barrett's esophagus remain free from cancer throughout their lifetimes. We will study the evolution of abnormalities in Barrett's esophagus that predict progression to cancer as well as how diet, the use of common drugs like aspirin, and other lifestyle choices can change the likelihood of developing this cancer. This will improve health care delivery by focusing cancer prevention and early detection efforts on those people most likely to benefit, while reassuring individuals at low risk and preventing exposure to invasive, potentially toxic interventions from which they have little chance of benefit.